Histamine H1 -antagonists

ABSTRACT

The invention provides 2-(3,5-disubstituted pyridylalkyl amino)-5-pyridylmethyl-4-pyrimidone derivatives which are useful as histamine H 1  -antagonists.

This invention relates to certain pyrimidone derivatives, compositionscontaining them and a method of blocking histamine H₁ -receptors byadministering them.

Histamine, a physiologically active compound endogenous in mammals,exerts its action by interacting with certain sites called receptors.One type of receptor is known as a histamine H₁ -receptor (Ash andSchild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histamine atthese receptors are inhibited by drugs commonly called "antihistamines"(histamine H₁ -antagonists ) a common example of which is mepyramine. Asecond type of histamine receptor is known as the H₂ -receptor (Black etal Nature 1972, 236, 385). The actions of histamine at these receptorsare not inhibited by mepyramine but are inhibited by burimamide.Compounds which inhibit the actions of histamine at histamine H₂-receptors are called histamine H₂ -antagonists.

U.S. Pat. No. 4,154,834 discloses compounds of general formula (I):##STR1## where Het is 2- or 4-imidazolyl optionally substituted by loweralkyl (preferably methy), halogen (preferably chlorine or bromine),trifluoromethyl or hydroxymethyl; 2-pyridyl optionally substituted byone or two groups (which may be the same or different) selected fromlower alkyl (preferably methyl), lower alkoxy (preferably methoxy),halogen (preferably chlorine or bromine), amino and hydroxy; 2-pyridylwith a phenyl, carbocyclic or cyclic ether ring containing 2 oxygenatoms fused to it; 2-thiazolyl; 3-isothiazolyl optionally substituted bychlorine or bromine; 3-(1,2,5)-thiadiazolyl optionally substituted bychlorine or bromine, or 2-(5-amino-1,3,4-thiadiazolyl); Y is sulphur ora methylene group; m is 0, 1 or 2 and n is 2 or 3 such that their sum is3 or 4 or when Y is methylene and Het is other than an imidazole ring,2; Z is hydrogen or lower alkyl (preferably methyl); X is oxygen orsulphur; A is a straight or branched alkylene chain containing from 1-5carbon atoms or --(CH₂)_(p) W(CH₂)_(q) -- where W is oxygen or sulphurand p and q are such that their sum is from 1 to 4; Het' is a 5 or 6membered heterocyclic ring selected from pyridine, pyridine-N-oxide,furan, thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine,pyrazine, pyridazine or thiadiazole, which ring is optionallysubstituted by one or two (which may be the same or different) of thegroups selected from lower alkyl, lower alkoxy, halo, hydroxy and amino,or Het' is a pyridine ring with a carbocyclic or cyclic ether ringcontaining two oxygen atoms fused to it, or Het' is a pyridine,imidazole or thiazole ring which has a benzene ring fused to it; andpharmaceutically acceptable salts thereof. These compounds are describedas having combined histamine H₁ - and H₂ -antagonist activity.

In particular U.S. Pat. No. 4,154,834 discloses compounds of formula (I)where Het is 2-pyridyl having a substituent in position 3, Y ismethylene and Het' is substituted pyridyl. It has now been found thatwhen the 2-pyridyl group Het has a second substituent in position 5 therelative level of H₁ to H₂ activity increases. A small number ofcompounds, which fall within the general class of compounds of formula(I), have now been found to be useful as histamine H₁ -antagonists, thatis, for the treatment of diseases for example bronchial asthma,rhinitis, hayfever and allergic eczema whose symptoms are mediatedthrough the action of histamine at H₁ -receptors.

Accordingly the present invention provides compounds of formula (II):##STR2## and pharmaceutically acceptable salts thereof; where R¹ is C₁₋₄alkyl, and R² is C₃₋₄ alkoxy, halogen, or amino; R³ is a C₁₋₃ alkylenegroup; and R⁴ is a 3-pyridyl, N-oxo-3-pyridyl, 6-methyl-3-pyridyl,N-oxo-6-methyl-3-pyridyl, or 6-hydroxymethyl-3-pyridyl group.

Examples of C₁₋₄ alkyl groups for R¹ are methyl, ethyl, n-propyl,iso-propyl, n-butyl and t-butyl.

Preferably R¹ is methyl.

Examples of C₃₋₄ alkoxy groups for R² are n-propoxy, iso-propoxy,n-butoxy and t-butoxy.

R² can represent any one of the halogens, fluorine, chlorine, bromine oriodine.

By way of example -R³ - can be methylene, 1,2-ethanediyl, or1,3-propanediyl.

Preferably R³ is 1,2-ethanediyl or 1,3-propanediyl.

Preferably R² is halogen (particularly bromine) or amino. Mostpreferably R² is amino.

Examples of compounds within the scope of this invention are:

2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone;

2-[4-(3-amino-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone;

2-[4-(3-n-propyloxy-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone;

2-[4-(3-chloro-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone;

2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-methyl-N-oxo-pyrid-3-ylmethyl)-4-pyrimidone;

2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone;

2-[5-(3-amino-5-methylpyrid-2-yl)pentylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone

and their pharmaceutically acceptable salts.

The compounds of formula (II) are shown and described as 4-pyrimidoneswhich exist in equilibrium with the corresponding 6-one tautomers. Thesecompounds also exist to a lesser extent as the hydroxy tautomers, andthe pyrimidine ring may also exist in the following tautomeric forms:##STR3##

It will be understood that all these tautomeric forms are within thescope of the present invention.

The compounds of formula (II) form pharmaceutically acceptable saltswith pharmaceutically acceptable salt-forming acids. Examples of theseacids are hydrochloric, sulphuric, hydrobromic, phosphoric, tartaric,citric, maleic, lactic, 2-hydroxyethanesulphonic, methanesulphonic,toluene-4-sulphonic, ethanedisulphonic, ethanesulphonic andcamphorsulphonic acids.

The compounds of this invention can be made by a process which comprisesreacting a compound of formula (III): ##STR4## or a salt thereof, whereR¹, R² and R³ are as defined with reference to formula (II) with acompound of formula (IV): ##STR5## where R⁴ is as defined with referenceto formula (II) and R⁶ is a group displaceable with amine, thereafteroptionally converting a compound of formula (II) so obtained where R⁴ isN-oxo-6-methyl-3-pyridyl, into the corresponding compound of formula(II) where R⁴ is 6-hydroxymethyl-3-pyridyl and optionally converting thecompound of formula (II) so obtained into a pharmaceutically acceptablesalt.

The compounds of formula (II) where R⁴ is methylN-oxo-6-methyl-3-pyridyl can be converted into the correspondingcompound of formula (II) where R⁴ is 6-hydroxymethyl-3-pyridyl byreacting them with an organic anhydride for example trifluoroaceticanhydride.

Pharmaceutically acceptable salts of compounds of formula (II) can beprepared by standard methods, for example by reacting a solution of thecompound of formula (II) with a solution of the acid.

Examples of groups R⁶ are C₁₋₄ alkylthio (particularly methylthio),benzylthio, chlorine, bromine and nitroamino. Preferably R⁶ isnitroamino.

The reaction can be carried out at an elevated temperature in theabsence of a solvent, for example at from 80° to 170°, preferably from120° to 140°, or in a solvent at an elevated temperature, for example atthe reflux temperature of the reaction mixture. The choice of solvent isaffected by solubility characteristics of the reactants and the natureof R⁶. Preferably the solvent is pyridine, a picoline or mixture ofpicolines, a C₁₋₄ alkanol, preferably ethanol or 1-propanol, a C₁₋₄alkanol, 1,2-ethanediol, a ketone, for example acetone or 2-butanone, ahigh boiling alkoxyaryl ether for example anisole, or a polar aproticsolvent, for example dimethylformamide, dimethylacetamide,dimethylsulphoxide, hexamethylphosphoramide, sulpholane, acetonitrile ornitromethane.

Compounds of formula (III): ##STR6## where R¹, R² and R³ are as definedwith reference to formula (II) can be prepared by reduction of thecorresponding cyano compound of formula (V): ##STR7## where R¹, R² andR³ are as defined with reference to formula (III) with a reducing agentwhich reduces cyano to amino without reducing the groups R¹ and R² in areaction medium which is inert to the reagents and product. For examplethe reducing agent can be lithium aluminium hydride or diborane. Thereaction medium can be a dialkyl ether for example diethyl ether or acyclic ether for example tetrahydrofuran or dioxan. Where the reducingagent is lithium aluminum hydride or diborane it will be appreciatedthat the reaction medium is anhydrous.

Compounds of formula (III) where R² is halogen can also be prepared fromthe corresponding compound of formula (III) where R² is amino. The aminogroup is converted into halogen by the Sandmeyer reaction, that is bydiazotisation of the amino group R² and displacing the diazo group withhalogen.

Compounds of formula (V) where R² is C₃₋₄ alkoxy can also be preparedfrom the corresponding compound of formula (V) where R² is amino byreaction with nitrous acid and thereafter with an alkylating agent.

Compounds of formula (V) where R² is amino can also be prepared byreducing the corresponding compound of formula (Va): ##STR8## Thereduction can be carried out by hydrogenation with stannous chloride.

Cyano compounds of formula (V) and (Va) can be prepared by reacting adisubstituted chloropyridine of formula (VI): ##STR9## where R¹ is aspreviously defined and R⁵ is nitro or a group R² as previously definedwith a malonic acid diester derivative of formula (VII): ##STR10## whereR³ is as previously defined and R are ester forming groups in thepresence of a strong base in an inert reaction medium and thereafterde-esterifying and de-carboxylating the product.

In particular the groups R can be ethyl.

In particular the strong base can be sodium hydride.

The reaction medium is one which is substantially inert to the reagentsand product. In particular the medium can be dry tetrahydrofuran.

The compound of formula (IV): ##STR11## are known or can be made byanalogy with known processes as disclosed in for example U.S. Pat. No.4,154,834 and European Patent Specification No. 17,679.

Compounds of formula (II) can also be prepared by reacting a guanidineof formula (XI): ##STR12## where R¹, R² and R³ are as defined withreference to formula (II) with a compound of formula (XII): ##STR13##where R⁴ is as defined with reference to formula (II) and R⁷ is C₁₋₄alkyl (particularly ethyl) benzyl or phenyl.

The reaction can be carried out by heating the guanidine of formula(XII) with the compound of formula (XIII) optionally in a solvent forexample an alcohol corresponding to the ester function in the compoundof formula (XIII) that is R⁷ OH, at an elevated temperature, preferablyin the presence of a base in particular the sodium alkoxide NaOR⁷corresponding to the ester function of the compound of formula (XII).

The guanidines of formula (XII) can be prepared by reacting an amine offormula (III) with a compound of formula (XIII): ##STR14## where R⁸ is aleaving group for example methylthio or 3,5-dimethylpyrazolyl.

The histamine H₁ -antagonist activity of the compounds of formula (II)can be demonstrated in vitro in the guinea pig ileum test. In this testan isolated portion of the guinea pig ileum is secured under tension(500 mg) between an anchorage and a transducer in a 10 ml tissue bathand immersed in magnesium free Tyrode solution with constant aeration ata temperature of 30° C. The output from the transducer is amplified. Theamplified output is in turn fed to a flat bed recorder. Measured amountsof histamine are added to the tissue bath so that the histamineconcentration increases step-wise until the force of the contractionreaches a maximum. The tissue bath is washed out and filled with freshmagnesium free Tyrode solution containing compound under test. Thesolution is left in contact with the tissue for 8 min. and measuredamounts of histamine are added again until a maximum contraction isrecorded. The assay is repeated with increasing concentrations of testcompound and the dose of histamine giving 50% of maximum contraction isnoted. A dose ratio (DR) was calculated by comparing the concentrationsof histamine required to produce 50% maximum response in the absence andin the presence of the antagonist. A plot of Log DR-1 against LOG D (theconcentration of compound under test) is made and the point ofintersection with the Log (DR-1) ordinate is taken as the measure of theactivity (pA₂ value). The compounds of Example 1-4, 6 and 7 have pA₂values of 8.0 or above.

The histamine H₂ -antagonist activity of the compounds of formula (II)can be demonstrated in vitro in the guinea pig atrium test. In this testa spontaneously beating isolated portion of the guinea pig right atriumis secured under tension (300 mg) between an anchorage and a transducerin a 15 ml tissue bath and immersed in McEwens solution with constantaeration at a temperature of 37° C. The output from the transducer isamplified. Output is in turn fed to a flat bed recorder. Measuredamounts of histamine are added to the tissue bath so that the histamineconcentration increases step-wise until the rate of beating reaches amaximum. The tissue bath is washed out and filled with fresh McEwenssolution containing compound under test. The solution is left in contactwith the tissue for 60 min. and measured amounts of histamine are addedagain until a maximum rate is recorded. The assay is repeated withincreasing concentrations of test compound and the dose of histaminegiving 50% of maximum rate is noted. A dose ratio (DR) was calculated bycomparing the concentrations of histamine required to produce 50%maximum response in the absence and in the presence of the antagonist. Aplot of Log DR-1 against LOG D (the concentration of compound undertest) is made and the point of intersection with the Log (DR-1) ordinateis taken as the measure of the activity (pA₂ value). The compounds ofExample 1-4, 6 and 7 have pA₂ values of less than 7.5.

The activity of compounds of formula (II) as histamine H₁ -antagonistscan be demonstrated in vivo by the inhibition of histamine inducedbronchoconstriction. Guinea pigs of either sex are anaesthetised byintraperitoneal injection of sodium pentobarbitone, 90 mg/kg. Thetrachea is cannulated. The animal is respired artificially with a fixedvolume of air just adequate to inflate the lungs. The pressure needed toinflate the lungs is monitored from the respiratory system using a lowpressure transducer. Intravenous injection of histamine causesdose-dependent increases in the pressure to inflate the lungs reflectingthe bronchoconstrictor action of histamine. Responses to histamine canbe antagonised using histamine H₁ -receptor antagonists.

Dose-response curves to histamine are established at 20, 40, 80, 160 and320 nmols/kg. Antagonists are then administered by intravenous injectionand 5 minutes later a new histamine dose-response curve is establishedincreasing the doses of histamine as necessary. The effect of theantagonist can be quantified by the displacement, to the right, of thehistamine dose-response curve, expressed as a dose-ratio. A series ofdoses of antagonists may be given to each animal allowing calculation ofdose-ratios for each dose of antagonist. The compounds of the Exampleshereafter cause displacement of histamine dose-response curves with adose-ratio of 10 at doses of less than 0.8 micromole kg⁻¹ i.v.

The activity of the compounds of formula (II) as histamine H₂-antagonists can be demonstrated in vivo by the inhibition ofhistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetised with urethane. This procedure is referredto in Ash and Schild, Brit. J. Pharmac. Chemother., 27, 247 (1966). Thecompounds of the Examples hereafter cause 50% inhibition of maximal acidsecretion at doses of 0.1 to 20 micromole kg⁻¹ i.v.

In order to use the compounds of the invention as histamine H₁-antagonists, they can be formulated as pharmaceutical compositions inaccordance with standard pharmaceutical procedure.

The invention also includes pharmaceutical compositions comprising acompound of formula (II) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

Compounds of formula (II) and their pharmaceutically acceptable saltscan be administered topically or systemically.

Topical formulations for administration to the skin include lotions andcreams. Topical formulations for administration to the respiratory tractinclude solutions for application via a nebulizer or as an aerosol, or amicrofine insufflatable powder. The active ingredient in aninsufflatable powder has a small particle size i.e. less than 50 micronsand preferably less than 10 microns. The active material is co-presentedwith a solid carrier for example lactose which has a particle size ofless than 50 microns.

Systemic administration can be achieved by rectal, oral or parenteraladministration. A typical suppository formulation comprises the activecompound with a binding agent and/or lubricating agent for examplegelatine or cocoa butter or other low melting vegetable waxes or fats.Typical parenteral compositions consist of a solution or suspension ofthe active material in a sterile aqueous carrier of parenterallyacceptable oil.

Compounds of formula (II) which are active when given orally can beformulated as syrups, tablets, capsules and lozenges. A syrupformulation generally consists of a suspension or solution of thecompound in a liquid carrier for example ethanol, glycerine or waterwith a flavouring or colouring agent. Where the composition is in theform of a capsule, the solid in granular form optionally with a bindingagent is encased in a gelatin shell. Where the composition is in theform of a tablet, any suitable pharmaceutical carrier routinely used forpreparing solid formulations can be used. Examples of such carriersinclude magnesium stearate, starch, lactose, glucose, sucrose, andcellulose. Preferably the composition is in unit dose form for example atablet, capsule or metered aerosol so that the patient may administer tohimself a single dose.

Where appropriate, small amounts of bronchodilators and anti-asthmaticsfor example sympathomimetic amines particularly isoprenaline,isoetharine, salbutamol, phenylephrine and ephedrine; xanthinederivatives particularly theophylline and aminophylline; andcorticosteroids particularly prednisolone and adrenal stimulantsparticularly ACTH can be included.

Each dosage unit for oral administration contains preferably from 1 to200 mg of a compound of formula (II) or a pharmaceutically acceptablesalt thereof calculated as the free base.

The invention also provides a method of blocking histamine H₁ -receptorswhich comprises administering to a subject an effective amount to blocksaid receptors of a compound of formula (II) or a pharmaceuticallyacceptable salt thereof.

The compounds of formula (II) and their pharmaceutically acceptablesalts will normally be administered to a subject in a pharmaceuticalcomposition as described above, for the treatment of rhinitis, hayfever,bronchial asthma or allergic eczema. An adult subject will receive anoral dose of between 15 mg and 400 mg and preferably between 15 mg and200 mg or an intravenous, subcutaneous or intramuscular dose of between1 mg and 50 mg, and preferably between 1 mg and 10 mg of a compound offormula (II) or a pharmaceutically acceptable salt thereof calculated asthe free base, the composition being administered 1 to 4 times per day.

The following Examples illustrate the invention.

EXAMPLE 1

(a) 2-(2-Cyanoethyl)malonic acid diethylester (40 g) was reacted withsodium hydride (4.4 gm) in tetrahydrofuran at 20° C.2-Chloro-5-methyl-3-nitro-pyridine (35 g) was added and the internaltemperature was raised to 100° C. (some tetrahydrofuran distilled off)over 4.25 hrs. The reaction mixture was partitioned between chloroformand water and treated with charcoal. Vacuum distillation of thechloroform extract and then chromatography (CHCl₃, silica column) of thedistillation residues gave 4-(5-methyl-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)-butyronitrile (24.5 g) as a yellow solid m.p. 48°-49° C.

(b) The product from Example 1(a) (13.9 g) was dissolved in a mixture ofethanol (568 ml) and sodium hydroxide solution (160 ml, molar) and afterhaving been left to stand for 4.5 days, the pH was lowered to 1.5 byaddition of hydrochloric acid. The reaction mixture was heated at 50° C.for 45 minutes, neutralised and the ethanol was removed in vacuo. Theproduct was extracted with chloroform to leave 6.7 gm of an orangesolid, which was dissolved in ether and treated with charcoal to give3-nitro-2-(3-cyanopropyl)-5-methylpyridine (6.45 g) m.p. 53°-55° C.

C₁₀ H₁₁ N₃ O₂ : Requires: C, 58.52; H, 5.40; N, 20.47; Found: C, 58.41;H, 5.54; N, 20.28;

(c) The product of Example 1(b) (11.07 g) was hydrogenated in ethanolwith palladium on charcoal (10%) at 140 kPa for 2.5 hours. The filteredsolution was concentrated to dryness, the residue was triturated withether to give 3-amino-2(3-cyanopropyl)-5-methylpyridine (9 g) m.p.84°-87° C.

(d) 3-Amino-2-(3-cyanopropyl)-5-methylpyridine (2.0 g) was reduced withlithium aluminium hydride (1.3 gm) in a mixture of tetrahydrofuran (110ml) and diethyl ether (40 ml) over 3.75 hrs, to give an amber oil (2.39g) which was partitioned between chloroform and water, the required3-amino-2-(4-aminobutyl)-5-methylpyridine (2.7 g) was obtained from theevaporation of the chloroform extracts obtained at pH 12 and 14, as anoil which crystallised slowly.

N.M.R. (CDCl₃): assignment, δ (p.p.m.), multiplicity; CH₂ CH₂ CH₂ NH₂,1.4-2.0, m; 5-methylpyridyl, 2.21, s; CH₂ (CH₂)₂ CH₂ NH₂, 2.6-2.9, m;3-aminopyridyl, ca 3.6, broad resonance; 4+6 pyridyl protons, 6.75+7.8,m;

(e) The product of Example 1(d) (0.5 g) in hydrobromic acid (48%) wasreacted with cuprous bromide and copper bronze. A solution of sodiumnitrite in water was added at 5° to 8° C. over 45 min., the reactionmixture was allowed to stir at 5° to 8° C. for a further hour and thanat room temperature for 3.5 hours. The reaction mixture was diluted withwater, and hydrogen sulphide gas was passed, while the pH wasprogressively raised to 11 by addition of sodium hydroxide solution. Theprecipitated copper salts were filtered off at intervals during theabove procedure. The product was then extracted at pH 11 with chloroformto give 3-bromo-2-(4-aminobutyl)-5-methylpyridine (0.5 g) as a brownoil.

N.M.R. (CDCl₃) assignment, δ(p.p.m.), multiplicity; CH₂ (CH₂)₂ CH₂ NH₂+NH₂, 1.5-1.9+1.81, m+s; 5-methylpyridyl, 2.30, s; --CH₂ (CH₂)₂ CH₂ NH₂,2.6-3.1, m; 4+6 pyridylprotons, 7.64+8.29, m×2;

(f) The product of Example 1(e) (0.48 g) and2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.65 g) wererefluxed in pyridine for 9.5 hours.

The pyridine was removed in vacuo and the residue was re-evaporated withn-propanol, triturated with chloroform, filtered and the solution waschromtographed on silica in chloroform methanol (10:1) to give2-[4-(3-bromo-5-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(0.52 g) m.p. 148.5°-151° C.

C₂₁ H₂₄ Br N₅ O: Requires: C, 57.01; H, 5.46; N, 15.83; Br, 18.06;Found: C, 56.98; H, 5.49; N, 15.77; Br, 18.31;

EXAMPLE 2

Reaction of 3-Amino-2-(4-aminobutyl)-5-methylpyridine, the product ofExample 1(d) (0.61 g), with2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.87 g) underconditions analogous to those in Example 1(f) gave2-[4-(3-amino-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(0.69 g) m.p. 86°-89° C. resolidifies and remelts at 171°-172° C.

C₂₁ H₂₆ N₆ O 1.42 H₂ O: Requires: C, 62.41; H, 7.10; N, 20.80; Found: C,62.32; H, 6.78; N, 20.70; (Weight loss 40°-90° C.=6.35%=1.42 H₂ O).

EXAMPLE 3

(a) A solution of 3-amino-2-(3-cyanopropyl)-5-methylpyridine [fromExample 1(c)] (1 g) in diluted sulphuric acid (0.78 ml conc. and 6.5 mlwater) was reacted with sodium nitrite (0.59 g in 3 ml water) between6°-10° C. The pH was brought to 6.5 with sodium hydroxide and theproduct was extracted with chloroform, chromatographed on silica inchloroform-methanol giving 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine(0.51 g) m.p. 132.5° C.

(b) A solution of 3-hydroxy-2-(3-cyanopropyl)-5-methylpyridine fromExample 3(a) (1.5 g), in dimethyl sulphoxide (11 ml) was first treatedwith sodium hydride (0.2 g) and then with n-propyl iodide in dimethylsulphoxide (3 ml) at 17°-20° C. After stirring for four hours at roomtemperature, the solvent was removed in vacuo and the residuepartitioned between chloroform and water, the chloroform extract wasevaporated to dryness to give3-n-propyloxy-2-(3-cyanopropyl)-5-methylpyridine (1.79 g) N.M.R.(CDCl₃), assignment, δ(p.p.m.), multiplicity; O(CH₂)₂ CH₃, 1.07; t; OCH₂CH₂ CH₃, 1.86; m; CH₂ CH₂ CN, 2.12, m; CH₂ CN, 2.40, m; 5-CH₃, 2.30, s;CH₂ (CH₂)₂ CN, 3.94, m; OCH₂, 3.91, t; 4-H pyridyl, 6.96, m; 6-Hpyridyl, 7.91, m;

(c) The product from Example 3(b) (1.64 g) was reduced with lithiumaluminium hydride (1.01 g) in diethyl ether (50 ml) and tetrahydrofuran(60 ml) over 5.5 hours to give3-n-propyloxy-2-(4-aminobutyl)-5-methylpyridine (1.23 g) as an oil.N.M.R. (CDCl₃) assignment, δ(p.p.m.), multiplicity; O(CH₂)₂ CH₃ 1.07, t;NH₂, 1.48, broad s; OCH₂ CH₂ CH₃ +CH₂ (CH₂)₂ CH₂ NH₂, 1.4-2.0, m; 5CH₃,2.28, s; CH₂ (CH₂)₂ CH₂ NH₂, 2.6-2.9, m; OCH₂, 3.9, t; 4H+6H pyridyl,6.89+7.9, m×2;

(d) Reaction of the product from Example 3(b) (0.6 g) with2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.78 g) underconditions analogous to those described in Example 1(f) gave2-[4-(3-n-propyloxy-5-methylpyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(0.280 g) m.p. 81°-85° C.

C₂₄ H₃₁ N₅ O₂ 1.5 H₂ O: Requires: C, 64.28; H, 7.62; N, 15.61; Found: C,64.14; H, 7.41; N, 15.38; (Loss of weight 40°-140° C.=6%=1.5 H₂ O).

EXAMPLE 4

(a) Reaction of 3-amino-2-(4-aminobutyl)-5-methylpyridine from Example1(d) (0.5 g) with sodium nitrite, cuprous chloride, copper bronze andhydrochloric acid under conditions analogous to those of Example 1(e)gave 3-chloro-2-(4-aminobutyl)-5-methylpyridine (0.43 g) as an oil.N.M.R. (CDCl₃) assignment δ(p.p.m.), multiplicity; NH₂, 1.56, s; CH₂(CH₂)₂ CH₂ NH₂, 1.4-1.9, m; 5--CH₃, 2.29, s; --CH₂ NH₂, 2.74; m; --CH₂(CH₂)₃ NH₂, 2.91, m; 4H+6H pyridyl protons, 7.45+8.24, m×2;

(b) Reaction of the product from Example 4(a) (0.4 g) with2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.63 g) underconditions analogous to those in Example 1(f) gave2-[4-(3-chloro-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(0.27 g) m.p. 140°-142° C.

C₂₁ H₂₄ Cl N₅ O 1.4 H₂ O: Requires: C, 59.58; H, 6.38; N, 16.54; Cl,8.37; Found: C, 59.79; H, 6.12; N, 16.58; Cl, 8.14; (loss of weight40°-70° C.=6%=1.4 H₂ O).

EXAMPLE 5

Reaction of the product from Example 1(e) (0.60 g) with2-nitroamino-5-(N-oxo-6-methylpyrid-3-ylmethyl)-4-pyrimidon (0.82 g)under conditions analogous to those described in Example 1(f) gave2-[4-(3-bromo-5-methylpyrid-2-yl)-butylamino]-5-(6-methyl-N-oxo-pyrid-3-ylmethyl)-4-pyrimidone(0.71 g), m.p. 175°-182° C.

EXAMPLE 6

Reaction of the product from Example 5 (0.36 g) in dichloromethane (3ml) with trifluoroacetic anhydride, for two days, followed by removal ofthe solvent in vacuo, dissolution of the residue in chloroform, washingof the chloroform solution with 10% sodium bicarbonate solution, andconcentrating the chloroform solution to dryness gave an oil 0.43 gm.This oil was chromatographed on silica in methanol-chloroform andrecrystallised from acetonitrile-water giving2-[4-(3-bromo-5-methylpyrid-2-yl)-butylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidone,(0.24 g) m.p. 150°-152° C.

C₂₁ H₂₄ Br N₅ O₂ 1.2 H₂ O: Requires: C, 52.54; H, 5.54; Br, 16.65; N,14.59; Found: C, 52.69; H, 5.41; Br, 15.90;N, 14.46; (loss of weight40°-150° C.=6%=1.2 H₂ O)

EXAMPLE 7

(a) 2-Chloro-5-methyl-3-nitro-pyridine (20 g) was reacted with2-(3-cyanopropyl)malonic acid diethyl ester under conditions analogousto those in Example 1(a). The reaction mixture was partitioned betweenwater and chloroform, the chloroform extract was dried, treated withcharcoal and filtered through a silica bed and then evaporated todryness to give2-[4-cyano-1,1-dicarbethoxybutyl]-3-nitro-5-methylpyridine (18.3 g) as ayellow oil. N.M.R. (CDCl₃) assignment, δ(p.p.m.), multiplicity; CO₂ CH₂CH₃ ×2, 1.2, t; --CH₂ CH₂ CH₂ CN, 1.3-2.0, m; --CH₂ CN, 2.37, m;5-methylpyridyl, 2.49, s; CO₂ CH₂ CH₃ ×2, 4.19, q; 4-pyridyl proton8.17, m; 6-pyridyl proton, 8.57, m;

(b) The product from Example 7(a) (5 g) was dissolved in a mixture ofethanol (206 ml) and sodium hydroxide solution (58 ml, molar) and leftin the dark for 6 days. The pH was lowered to 1.5 by the addition ofhydrochloric acid, the reaction mixture was heated in a water bath at50° C. for 75 mins, pH raised to 7, and ethanol was distilled off. Theproduct was extracted with chloroform to give an oil (4.4 g). This oilwas extracted with dilute hydrochloric acid. (16 ml of 1.5 N)re-extracted with more dilute hydrochloric acid and the combined acidextracts were then extracted with chloroform to give3-nitro-2-(3-cyanobutyl)-5-methylpyridine (1.61 g) as a yellow oil.N.M.R. (CDCl₃) assignment, δ(p.p.m.), multiplicity; --CH₂ CH₂ CH₂ CN,1.5-2.2, m; 5--CH₃, 2.43, s; CH₂ CN, 2.43, m; CH₂ (CH.sub. 2)₃ CN, 3.11,m; 4--H pyridine, 8.02, m; 6--H pyridine, 8.58, m;

(c) Hydrogenation of the product of Example 7(b) under conditionsanalogous to those of Example 1(c) gave3-amino-2-(3-cyanobutyl)-5-methylpyridine (1.21 g) m.p. 112°-114° C.

(d) 3-Amino-2-(3-cyanobutyl)-5-methylpyridine (1.13 g) was reduced withlithium aluminium hydride (0.8 g) in a mixture of tetrahydrofuran (100ml) and diethyl ether (10 ml) over 3.5 hours. The crude product wasobtained as a yellow oil (1.23 g) which was chromatographed inammonia-ethyl acetate-ethanol on silica to give3-amino-2-(5-aminopentyl)-5-methylpyridine (0.41 g) as a yellow waxysolid. N.M.R. (CDCl₃) assignment, (p.p.m.), multiplicity; CH₂ (CH₂)₃ CH₂NH₂, ca 1.5, m; CH₂ NH₂, 1.73, broad s; 5--CH₃, 2.22, s; CH₂ (CH₂)₃ CH₂NH₂, 2.5-2.9, m; 3--NH₂, ca. 3.6, broad resonance; 4--H pyridyl, 6.76,m; 6---H pyridyl, 7.81, m.

(e) Reaction of the product of Example 7(d) (0.32 g) with2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.56 g) underconditions analogous to those in Example 1(f) gave2-[5-(3-amino-5-methylpyrid-2-yl)-pentylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone(0.36 gm) m.p. 161°-163° C.

C₂₂ H₂₈ N₆ O 2.8H₂ O: Requires: C, 59.67; H, 7.62; N, 18.98. Found: C,59.71; H, 7.65; N, 18.92 (weight loss 50°-90° C.=11.36%=2.8H₂ O)

EXAMPLE 8

A pharmaceutical composition for oral administration is preparedcontaining

    ______________________________________                                                              % by weight                                             ______________________________________                                                  2-[4-(3-bromo-5-methylpyrid-2-yl)-                                                                  55                                                      butylamino]-5-(6-methylpyrid-3-yl-                                  A         methyl)-4-pyrimidone                                                          Dibasic calcium phosphate dihydrate                                                                 20                                                      Approved coloring agent                                                                             0.5                                                     Polyvinylpyrrolidone  4.0                                                     Microcrystalline Cellulose                                                                          8.0                                                     Maize Starch          8.0                                           B         Sodium glycollate     4.0                                                     Magnesium Stearate    0.5                                           ______________________________________                                    

by mixing together the ingredients A (substituting lactose ormicrocrystalline cellose for dibasic calcium phosphate dihydrate ifdesired), adding a concentrated solution of polyvinylpyrrolidone andgranulating, drying and screening the dried granules; adding theingredients B to the dried granules and compressing the mixture intotablets containing 5 mg, 25 mg or 50 mg of the free base.

Other compounds of the invention, for example those specificallydescribed in Examples 2 to 7 can be formulated into pharmaceuticalcompositions by a similar procedure.

EXAMPLE 9

A pharmaceutical composition for injectable administration is preparedby forming a solution of2-[4-(3-bromo-5-methyl-pyrid-2-yl)-butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidonehydrochloride salt in sterile water to give a 1 to 5% w/w solution. Thesolution is clarified by filtration and filled into vials which aresealed and sterilised. A suitable vial contains 2 ml of the solution.

I claim:
 1. A compound of formula (II): ##STR15## or a pharmaceuticallyacceptable salt thereof; where R¹ is C₁₋₄ alkyl, and R² is C₃₋₄ alkoxy,halogen, or amino; R³ is a C₁₋₃ alkylene group; and R⁴ is a 3-pyridyl,N-oxo-3-pyridyl, 6-methyl-3-pyridyl, N-oxo-6-methyl-3-pyridyl or6-hydroxymethyl-3-pyridyl group.
 2. A compound according to claim 1where R¹ is methyl.
 3. A compound according to claim 1 where R² is aminoor halogen.
 4. A compound according to claim 3 where R² is amino.
 5. Acompound according to claim 1 where R⁴ is 6-methyl-pyrid-3-yl.
 6. Acompound according to claim 1 which is2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 1 which is2-[4-(3-amino-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1 which is2-[4-(3-n-propyloxy-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 9. A compound accordingto claim 1 which is2-[4-(3-chloro-5-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone or a pharmaceutically acceptable saltthereof.
 10. A compound according to claim 1 which is2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-methyl-N-oxo-pyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 which is2-[4-(3-bromo-5-methylpyrid-2-yl)butylamino]-5-(6-hydroxymethylpyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 which is2-[5-(3-amino-5-methylpyrid-2-yl)pentylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidoneor a pharmaceutically acceptable salt thereof.
 13. A hydrochloride saltof a compound of formula (II) according to claim
 1. 14. A pharmaceuticalcomposition having histamine H₁ -antagonist activity comprising aneffective amount of a compound according to claim 1 and apharmaceutically acceptable carrier.
 15. A method of blocking histamineH₁ -receptors which comprises administering to a subject an effectiveamount to block said receptors of a compound according to claim 1.